Modelling and simulation of retroviral proteins and nanobiocomposites

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Sergey Shityakov's PhD defence

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Molecular modelling and simulation of retroviral proteins and nanobiocomposites University of Würzburg , Biocenter , Department of Bioinformatics, Würzburg , Germany Sergey Shityakov Würzburg , 2011

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Thesis Outlook Molecular dynamics simulation of SWCN with lipid membrane fragments ( Shityakov and Dandekar , NANO, 2011). HIV-1 Integrase and Transportin-SR2 interaction ( Shityakov et al., OJB, 2010). Lead expansion and virtual screening of HIV-1 protease inhibitors using pharmacophore -shape similarity scoring function ( Shityakov and Dandekar , Bioinformation , 2009). Role of the cPPT in retroviral nuclear import ( Shityakov and Rethwilm , unpublished) .

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Part I Structural and docking analysis of HIV-1 I ntegrase and Transportin-SR2 interactions: Is this a more general and specific route for retroviral nuclear import?

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Sherman et al., Micro. Inf , 2002 TR

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Structure of TR-SR1 and HIV-1 IN Imasaki et al., Cell, 2007

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Rank Solution Number Global Energy Attractive VdW 1 Repulsive VdW ACE HBE 1 6 -0.50 -20.21 15.78 3.71 0.00 2 3 -0.37 -39.79 29.36 4.69 -5.05 3 2 2.06 -1.72 0.00 0.12 -0.80 4 5 5.19 -22.87 9.68 -4.69 0.00 5 4 9.72 -25.44 19.09 6.44 -1.79 6 7 13.03 -6.27 0.14 4.51 0.00 7 1 14.98 -3.89 1.69 -1.13 0.00 TR-SR1/SR2 3D superimposition and docking Shityakov et al., OJB, 2010

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donor ‘NLS' ⟹ acceptor ‘H8-loop' residues in close contact donor ‘H8-loop' ⟹ acceptor ‘NLS' residues in close contact Ile 161 ⟹ Asp 332, Lys 334, Ile 333, Asp 328 Gln 168 ⟹ Arg 336 His 171 ⟹ Ser 355 Val 165 ⟹ Arg 336 Arg 166 ⟹ Asp 361 Lys 334 ⟹ Ile 161 Arg 336 ⟹ Gln 168, Val 165 Asp 361 ⟹ Arg 166 Asp 328 ⟹ Ile 161 Asp 332 ⟹ Ile 161 Ser 355 ⟹ His 171 Ile 333 ⟹ Ile 161 Flexible docking of TR-SR2 H8-loop and HIV-1 IN NLS Shityakov et al., OJB, 2010

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The H8-loop of the TR-SR2 and the HIV-1 NLS H8-loop Area Acc. (%) HI IN NLS Area Acc. (%) HI Asp 328 130.255 80.3 -3.5 Ile 161 157.887 92.2 4.5 Asp 332 106.409 65.6 -3.5 Val 165 71.374 48.0 4.2 Ile 333 111.333 65.0 4.5 Arg 166 93.843 38.5 -4.5 Lys 334 115.095 54.4 -3.9 Gln 168 125.090 66.9 -3.5 Arg 336 210.727 86.4 -4.5 His 171 127.643 66.6 -3.2 Ser 355 74.924 100.0 -0.8 Asp 361 104.115 64.2 -3.5 Shityakov et al., OJB, 2010

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Shityakov et al., OJB, 2010

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Summary Highly similar sequences of TR-SR1 and TR-SR2 have different 3D folding domain structures. Rigid protein-protein docking reveals the interaction of TR-SR2 Ran-GDP BD with HIV-1 IN CCD. Flexible protein-protein docking detects the interaction mode between NLS of HIV-1 IN CCD and H8-loop of TR-SR2 Ran-GDP binding domain. Highly accessible and hydrophilic amino acids are playing an important role in H-bond formation between TR-SR2 and HIV-1 IN .

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Part II Molecular dynamics simulation of POPC and POPE lipid membrane fragments enforced by an intercalated single-wall carbon nanotube

Schematic representation of the simulated systems:

Schematic representation of the simulated systems Shityakov and Dandekar, NANO, 2011

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Shityakov and Dandekar, NANO, 2011

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Shityakov and Dandekar, NANO, 2011

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Comparative characteristics of the RMSD values of the different simulated structures at different temperature parameters Shityakov and Dandekar, NANO, 2011

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Comparative characteristics of the RMSF values of the different simulated structures and substructures at different temperature parameters Shityakov and Dandekar, NANO, 2011

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Summary The entire single-wall carbon nanotube structure remains intact and stable through the molecular dynamics simulation. Lipid membrane fragments maintain integrity at 300K but very unstable at high temperatures (300-400K, 400K). POPC lipid membrane fragment is more stable than POPE but has less ‘adaptation’ to transition temperature (300-400K). An intercalated SWCNT has a stabilizing impact on the lipid membrane fragments MD.

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Acknowledgments Prof. Dr . Thomas Dandekar ( Biocenter , University of Würzburg ) Prof. Dr. Axel Rethwilm (Institute of Virology and Immunobiology , University of Würzburg ) Dr. Tatiana Wiktorowicz (Institute of Virology and Immunobiology , University of Würzburg ) Dr. Rebecca Wade and Dr. Rob Russell (EMBL, Heidelberg)

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Thank you for your attention

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